Metallic materials used for medical devices (for example, an (auxiliary) artificial heart, an artificial valve, a stent, a pacemaker, etc.) almost satisfy the conditions with respect to mechanical properties, but have not necessarily sufficient biocompatibility (including blood compatibility). When blood components come into contact with a surface of a medical device to form thrombus because of insufficient biocompatibility of the medical device, inhibition of blood flow arises, resulting in serious harm to the human body. Therefore, in clinical practice, a drug capable of inhibiting a biological defense reaction is required in a therapeutic action using a medical device and the side effect caused by use of this drug over a long period constitutes a large problem. A biocompatible (including blood compatibility) material is indispensable to develop a medical device which can be used in the state of being embedded in the living body over a long period.
In current medical practice, a method using a biologically active substance capable of inhibiting thrombus formation is used so as to impart antithrombotic properties to a surface of a medical device, for example, an artificial organ. This method includes, for example, a method of immobilizing a biologically active substance such as urokinase having a function of dissolving thrombus thus formed, heparin capable of inhibiting a function of thrombin as a coagulation factor, or prostaglandin as a platelet activation inhibitor to a surface of a material. However, the side effect caused by these drugs cannot be neglected and is a large problem. It is very difficult to control the release rate of the drug and also the effect cannot be expected after release of the drug. Furthermore, a non-biocompatible polymer, for example poly(lactide-co-ε-caprolactone), poly(n-butyl methacrylate) or poly(dimethylsiloxane) is often used in a drug eluting type medical device (particularly stent) and, after elution of the drug, a polymer remaining on a stent surface may cause inflammatory reaction and thrombus formation. Furthermore, there is reported a problem that endothelialization does not occur on the stent surface.
In order to impart antithrombotic properties to a surface of a medical device, for example, an artificial organ, a method utilizing a biological reaction is employed. That is, it is a method in which coagulation factors and platelets are moderately aggregated to a surface of a material to form a thrombus membrane, and endothelial cells constituting a vascular wall are engrafted on the thrombogenic membrane as a footing and a thin neointima is formed on the surface of the material by further growth of the endothelial cells. However, since thrombus may occur for about one month after surgery during which the medical device has been completely coated with endothelial cells, it becomes necessary to administer an antiplatelet drug and thus the side effect caused by the drug cannot be neglected.
There is also employed a method in which antithrombotic properties are obtained by surface properties of the material per se without using a biologically active substance or a drug. By the way, thrombus formation occurs due to an adsorption of a plasma protein and a subsequent activation of platelets, and the adsorption of the plasma protein onto the surface of the material physicochemically proceeds. Therefore, in order to decrease the interaction between the material and blood, the surface of the material is converted into the state almost as close to blood as possible by reforming the surface of the material.
Such a reforming method includes, for example, a method in which a water-soluble polymer is bonded by a coupling reaction utilizing functional groups such as hydroxyl and amino groups of the surface of the material.
For example, a method for immobilizing a copolymer consisting of allylamine and a monomer having a phosphorylcholine group to a medical material is disclosed (Patent Document 1). However, when the copolymer is used, there arises a problem that the content of the phosphorylcholine group decreases and the resulting material is inferior in biocompatibility (including blood compatibility), hydrophilicity and surface lubricity. In contrast, when the content of the phosphorylcholine group in the copolymer is excessive, there arises a problem that the copolymer becomes soluble in water and adhesion is not maintained when used for a long time. Actually, an artificial heart made of metallic titanium coated with an MPC copolymer contains only 30% of MPC in the MPC copolymer because of a problem of solubility (Non-Patent Document 1).
Another reforming method includes a method in which peroxide as a polymerization initiator is produced on a surface of a material by irradiating with ultraviolet rays, electric beams or ion beams in the presence of oxygen, and then a water-soluble vinyl monomer is subjected to radical polymerization to form a water-soluble polymer chain on the surface of the material. It is reported that this water-soluble polymer chain prevents a protein from being directly contacted with the surface of the material and inhibits the adsorption of the protein onto the surface of the material.
For example, Kazuhiko Ishihara et al. succeeded in an improvement of anti-protein adsorption property by MPC-grafting as a monomer on a polyethylene surface through irradiation with ultraviolet rays. However, this is a technology concerning a polymer substrate and it is impossible to easily reform a surface of a metal substrate. There is also disclosed a report that a poly(MPC) layer formation on a cobalt-chromium alloy is carried out with use of 4-methacryloxyethyl trimellitate anhydride (4-META) as a binder, and as a result, excellent hydrophilicity and lubricating properties are obtained (Non-Patent Document 2). However, there is also reported a problem that the cobalt-chromium alloy cannot be completely coated.
Taking a dental implant into account, there has conventionally been carried out a prosthetic treatment with retrievable partial denture or bridge denture for repairing a loss of teeth due to periodontal diseases and dental caries. However, retrievable partial denture has an aesthetic problem attributed from a metal hook and a problem of providing a feeling of resistance to implementation, while bridge denture has a problem that burden for abutment tooth to be grinded cannot be avoided. A dental implant treatment has attracted special interest recently as a prosthetic treatment and is one of selection choices, and the number of cases has remarkably increased. In loss of teeth due to fracture of an alveolar bone, teeth are lost together with the alveolar bone around teeth and thus bone width and bone height enough to carry out embedding of implant were not often obtained. However, it has become possible to apply a bone grafting method, a guided bone regeneration (GBR) method, a bone lengthening method, a bone prosthetic material, and a bone augmentation method utilizing cytokines, thus increasing the number of cases of application of a dental implant. In some cases, it becomes possible to impart an occlusion function through embedding due to one-stage implant and mounting of an upper structure at an initial stage after embedding, by improving surface properties of an implant or controlling a load on an implant body after embedding. Establishment of a method of early and surely acquiring oseointegration remarkably contributes to stabilization of the occlusion function of the dental implant. However, even if osseointegration is acquired, it is impossible to persistently avoid the circumstance in which the implant body as foreign matters penetrates through the epithelium. Therefore, how plaque deposition in this gingival penetration portion is inhibited and inflammation around the implant body is prevented, was an important object for enabling the dental implant to function over a long period. Particularly in two-stage implant, the micro-gap existing between the abutment and the fixture bonding portion makes it easy to cause inflammation around the implant. Also, local bone resorption temporarily occurs due to a removal of the bond formed on so-called healing cap or the top portion of the implant body during secondary surgery, and thus down growth of gingival epithelia is likely to occur, thus leading to the state where plaque deposition is likely to occur, and esthetics may sometimes deteriorate, which is a clinical problem.
Patent Document 1: International Publication No. WO 01-05855
Non-Patent Document 1: In Vivo Evaluation of a MPC Polymer Coated Continuous Flow Left Ventricular Assist System, ARTIFICIAL ORGANS, VOL. 27, No. 2, 2003
Non-Patent Document 2: High lubricious surface of cobalt-chromium-molybdenum alloy prepared by grafting poly(2-methacryloyloxyethyl phosphorylcholine), Biomaterials, VOL. 28, 2007